O gene da adiponectina e o risco cardiovascular em pacientes com diabetes tipo 2: uma revisão das evidiencias

Diabetic patients have a 3-fold higher risk of developing atherosclerosis and its clinical complications as compared to non-diabetic individuals. Part of the cardiovascular risk associated with diabetes is probably due to genetic determinants influencing both glucose homeostasis and the development of atherosclerosis. However, type 2 diabetes frequently coexists with other cardiovascular risk factors like arterial hypertension, central obesity and dyslipidemia. Genetic variability affecting many areas such as lipid and energy metabolisms, hypertension and haemodynamic mechanisms, blood clotting homeostasis, inflammation, and matrix turnover in the vascular wall will have an impact on the development of macrovascular complications in diabetic patients. Adiponectin is abundantly secreted by adipocytes. It plays important roles in lipid and glucose metabolisms and has direct anti-inflammatory and anti-atherogenic effects. In this review, we summarize recent data from the literature suggesting an implication of allelic variations of the adiponectin gene (ADIPOQ) in the genetic determinants of cardiovascular disease in diabetic subjects.Os pacientes com diabetes apresentam risco três vezes maior de desenvolverem aterosclerose e suas complicações quando comparados a indivíduos sem hiperglicemia. Parte desse risco associado ao diabetes é provavelmente relacionado a determinantes genéticos que influenciam tanto a homeostase glicídica quanto o desenvolvimento da aterosclerose. Entretanto, o diabetes tipo 2 freqüentemente coexiste com outros fatores de risco cardiovascular, tais como hipertensão arterial, obesidade central e dislipidemia. A variabilidade genética interfere em várias áreas tais como o metabolismo lipídico, o metabolismo energético, hipertensão, mecanismos hemodinâmicos, mecanismos de coagulação, inflamação e na formação da matriz na parede vascular, que podem estar envolvidos nas complicações macrovasculares dos pacientes com diabetes. A adiponectina é secretada com abundância pelos adipócitos. Apresenta importante papel no metabolismo lipídico e glicídico, tendo ação direta tanto antiinflamatória quanto anti-aterogênica. Na atual revisão, nós resumimos os dados recentes da literatura que sugerem uma implicação de variantes alélicas do gene da adiponectina (ADIPOQ) que podem estar envolvidos na determinação genética da doença cardiovascular em indivíduos com diabetes.São Paulo University Laboratory of Cellular and Molecular EndocrinologyFederal University of São Paulo Laboratory of Molecular EndocrinologyFleury InstituteINSERMUniversité Paris 7UNIFESP, Laboratory of Molecular EndocrinologySciEL

The common-866G > A variant in the promoter of UCP2 is associated with decreased risk of coronary artery disease in type 2 diabetic men

OBJECTIVE-Uncoupling protein 2 (UCP2) is a physiological downregulator of reactive oxygen species generation and plays an antiatherogenic role in the vascular wall. A common variant in the UCP2 promoter (-866G>A) modulates mRNA expression, with increased expression associated with the A allele. We investigated association of this variant with coronary artery disease (CAD) in two cohorts of type 2 diabetic subjects.RESEARCH DESIGN and METHODS-We studied 3,122 subjects from the 6-year prospective Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria, Cardiovascular Events, and Ramipril (DIABHYCAR) Study (14.9% of CAD incidence at follow-up). An independent, hospital-based cohort of 335 men, 52% of whom had CAD, was also studied.RESULTS-We observed an inverse association of the A allele with incident cases of CAD in a dominant model (hazard risk 0.88 [95% CI 0.80-0.96]; P = 0.006). Similar results were observed for baseline cases of CAD. Stratification by sex confirmed an allelic association with CAD in men, whereas no association was observed in women. All CAD phenotypes considered-myocardial infarction, angina pectoris, coronary artery bypass graft (CABG), and sudden death-contributed significantly to the association. Results were replicated in a cross-sectional study of an independent cohort (odds ratio 0.47 [95% CI 0.25-0.89]; P = 0.02 for a recessive model).CONCLUSIONS-The A allele of the -866G>A variant of UCP2 was associated with reduced risk of CAD in men with type 2 diabetes in a 6-year prospective study. Decreased risk of myocardial infarction, angina pectoris, CABG, and sudden death contributed individually and significantly to the reduction of CAD risk. This association was independent of other common CAD risk factors.INSERM, Fac Med Xavier Bichat, U695, F-75018 Paris, FranceCochin Hosp, AP HP, Dept Immunol & Diabetol, Paris, FranceUniv São Paulo, Lab Cellular & Mol Endocrinol, São Paulo, BrazilUniversidade Federal de São Paulo, Mol Endocrinol Lab, São Paulo, BrazilFed Fac Fdn Med Sci Porto Alegre, Post Grad Program Med Sci, Porto Alegre, RS, BrazilHop La Pitie Salpetriere, Dept Cardiol, AP HP, Paris, FranceUniv Paris 07, Paris, FranceUniv Paris 05, Paris, FranceUniversidade Federal de São Paulo, Mol Endocrinol Lab, São Paulo, BrazilWeb of Scienc

Decreased insulin secretion and increased risk of type 2 diabetes associated with allelic variations of the WFS1 gene: the Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study

We investigated associations of allelic variations in the WFS1 gene with insulin secretion and risk of type 2 diabetes in a general population prospective study.We studied 5,110 unrelated French men and women who participated in the prospective Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study. Additional cross-sectional analyses were performed on 4,472 French individuals with type 2 diabetes and 3,065 controls. Three single nucleotide polymorphisms (SNPs) were genotyped: rs10010131, rs1801213/rs7672995 and rs734312.We observed statistically significant associations between the major alleles of the three variants and prevalent type 2 diabetes in the DESIR cohort at baseline. Cox analyses showed an association between the G-allele of rs10010131 and incident type 2 diabetes (HR 1.34, 95% CI 1.08-1.70, p = 0.007). Similar results were observed for the G-allele of rs1801213 and the A-allele of rs734312. the GGA haplotype was associated with an increased risk of diabetes as compared with the ACG haplotype (HR 1.26, 95% CI 1.04-1.42, p = 0.02). We also observed statistically significant associations of the three SNPs with plasma glucose, HbA(1c) levels and insulin secretion at baseline and throughout the study in individuals with type 2 diabetes or at risk of developing diabetes. However, no association was observed in those who remained normoglycaemic at the end of the follow-up. Associations between the three variants and type 2 diabetes were replicated in cross-sectional studies of type 2 diabetic patients in comparison with a non-diabetic control group.The most frequent haplotype at the haplotype block containing the WFS1 gene modulated insulin secretion and was associated with an increased risk of type 2 diabetes.Societe Francophone du Diabete (SFD - Alfediam)Association Diabete Risque Vasculaire (ADRV), FranceCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)INSERMCNAMTSLillyNovartis PharmaSanofi-AventisINSERM (Reseaux en Sante Publique, Interactions entre les determinants de la sante)Association Diabete Risque VasculaireFederation Francaise de CardiologieLa Fondation de FranceALFEDIAMONIVINSArdix MedicalBayer DiagnosticsBecton DickinsonCardionicsMerck SanteNovo NordiskPierre FabreRocheTopconUniv Paris 07, INSERM, Res Unit 695, F-75018 Paris, FranceFed Univ Hlth Sci Porto Alegre, Postgradut Program Hlth Sci, Porto Alegre, RS, BrazilUniversidade Federal de São Paulo, Mol Endocrinol Lab, São Paulo, BrazilAssistance Publ Hop Paris Cochin Hosp, Dept Immunol & Diabetol, Paris, FranceUniv Paris 05, UFR Med, Paris, FranceUniv Paris 07, UFR Med, Paris, FranceAssistance Publ Hop Paris Bichat Hosp, Dept Endocrinol Diabetol & Nutr, Paris, FranceInst Inter Reg Sante IRSA, La Riche, FranceINSERM, U1018, CESP, Ctr Res Epidemiol & Populat Hlth, Villejuif, FranceUniv Paris 11, UMRS 1018, Villejuif, FranceUniversidade Federal de São Paulo, Mol Endocrinol Lab, São Paulo, BrazilCAPES: 1798-09-0Web of Scienc

Implication de 5 gènes candidats exprimés dans les cellules bêta-pancréatiques dans les déterminants génétiques du diabète de type 2 et de ses complications vasculaires

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

The Gly482Ser polymorphism in the peroxisome proliferator-activated receptor-gamma coactivator-1 gene is associated with hypertension in type 2 diabetic men

Aims/hypothesis. Peroxisome proliferator-activated receptor-gamma coactivator-1 (PPARGC1) acts as a cofactor for several nuclear hormone receptors in many tissues and organs implicated in blood pressure regulation. Here, we assessed the association between the Gly482Ser variant of PPARGC1 and the arterial hypertension frequently found in subjects with type 2 diabetes.Methods. We studied a group of 479 men and 253 women with type 2 diabetes. Arterial hypertension was present in 70% of the men and in 73% of the women. Genotypes were examined by PCR restriction fragment length polymorphism. A logistic regression analysis was performed to assess the covariables associated with arterial hypertension.Results. There was an association between Ser allele homozygosis and arterial hypertension in type 2 diabetic men (odds ratio of 2.52 vs Gly allele homozygosis; 95% CI: 1.32-5.00; p=0.0064), but not in women. the prevalence of arterial hypertension in type 2 diabetic men was 77% vs 73% vs 67% for Ser-Ser, Gly-Ser and Gly-Gly carriers respectively (p=0.021). Age, BMI, the use of insulin, and triglyceride and creatinine levels were also independently associated with arterial hypertension in this cohort.Conclusions/interpretation. We have observed a sex-specific association between the PPARGC-1 gene Gly482Ser polymorphism and arterial hypertension in type 2 diabetic men. Further studies are needed to investigate the genetic, biochemical and pathophysiological basis of this allelic association.Hop St Vincent de Paul, INSERM, Res Unit 561, F-75014 Paris, FranceUniversidade Federal de São Paulo, Mol Endocrinol Lab, São Paulo, BrazilCochin Hosp, Dept Immunol & Diabetol, Paris, FranceHop St Antoine, Mol Biol Unit, F-75571 Paris, FranceUniversidade Federal de São Paulo, Mol Endocrinol Lab, São Paulo, BrazilWeb of Scienc

Allelic variations in the vitamin D receptor gene, insulin secretion and parents' heights are independently associated with height in obese children and adolescents

Polymorphisms in the VDR gene were reported to be associated with variations in intrauterine and postnatal growth and with adult height, but also with other traits that are strongly correlated such as the BMI, insulin sensitivity, insulin secretion and hyperglycemia. Here, we assessed the impact of VDR polymorphisms on body height and its interactions with obesity- and glucose tolerance-related traits in obese children and adolescents. We studied 173 prepubertal (Tanner's stage 1) and 146 pubertal (Tanner's stages 2-5) obese children who were referred for a weight-loss program. Three single nucleotide polymorphisms were genotyped: rs1544410 (BsmI), rs7975232 (ApaI) and rs731236 (TaqI). BsmI and TaqI genotypes were significantly associated with height in pubertal children, but the associations did not reach statistical significance in prepubertal children. In stepwise regression analyses, the lean body mass, insulin secretion, BsmI or TaqI genotypes and the father's and the mother's height were independently and positively associated with height in pubertal children. These covariables accounted for 46% of the trait variance. The height of homozygous carriers of the minor allele of BsmI was 0.65 z-scores (4 cm) higher than the height of homozygous carriers of the major allele (P=.0006). Haplotype analyses confirmed the associations of the minor alleles of BsmI and TaqI with increased height. In conclusion, VDR genotypes were significantly associated with height in pubertal obese children. The associations were independent from the effects of confounding traits, such as the body fat mass, insulin secretion, insulin sensitivity and glucose tolerance. (C) 2012 Elsevier Inc. All rights reserved.FAPESP, BrazilFAPESP (Brazil)Societe Francophone du Diabete (SFD - Alfediam)Societe Francophone du Diabete (SFD Alfediam)Association Diabete Risque Vasculaire (ADRV), FranceAssociation Diabete Risque Vasculaire (ADRV), FranceCNPq, BrazilCNPq (Brazil

Two novel mutations in the EIF2AK3 gene in children with Wolcott-Rallison syndrome

Wolcott-Rallison syndrome (WRS, OMIM 226980) is a rare autosomal recessive disorder characterized by permanent neonatal diabetes mellitus, epiphyseal dysplasia, and other multisystemic clinical manifestations. We described two novel mutations in the EIF2AK3 gene in two consanguineous families with WRS from Brazil and Morocco. We have observed in case 1 a homozygous C > T replacement at base pair c.1192 at exon 7, generating a stop codon at position 398 (Gln398Stop). Both of his parents were found to be heterozygous for the mutation. We detected in both parents of case 2, a deceased Moroccan girl, a duplication of base pair c.851A at exon 5 (c.851dupA) leading to a frameshift and a stop codon at position 285 (p.Pro285AlafsX3). Both cases 1 and 2 had neonatal diabetes mellitus, multiple epiphyseal dysplasia, and growth delay, and presented episodes of acute hepatic dysfunction. Case 1 presented central hypothyroidism, developmental delay, and mild mental retardation. Case 2 presented a fatal episode of acute renal failure. the clinical phenotype associated with the syndrome can be variable, but a combination of infancy-onset diabetes mellitus, multiple epiphyseal dysplasia, and hepatic and/or renal dysfunction is the mainstay of diagnosis.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Societe Francophone du Diabete (SFD - Alfediam)Universidade Federal de São Paulo, Endocrinol Unit, São Paulo, BrazilHop Bichat Claude Bernard, AP HP, Lab Biochim Hormonale & Genet, F-75877 Paris 18, FranceUniv Paris 07, UFR Med Site, F-75018 Paris, FranceHop Enfants, CHU Ibn Rochd, Serv Pediat 2, Casablanca, MoroccoUniv São Paulo, Hosp Clin, Inst Crianca, Endocrine Pediat Unit, São Paulo, BrazilINSERM, Res Unit 695, Paris, FranceUniv São Paulo, Hosp Clin, Dept Neurol, São Paulo, BrazilFleury Med & Saude, São Paulo, BrazilUniversidade Federal de São Paulo, Endocrinol Unit, São Paulo, BrazilCAPES: 1798-09-0Web of Scienc

The common-866G > A variant in the promoter of UCP2 is associated with decreased risk of coronary artery disease in type 2 diabetic men

OBJECTIVE-Uncoupling protein 2 (UCP2) is a physiological downregulator of reactive oxygen species generation and plays an antiatherogenic role in the vascular wall. A common variant in the UCP2 promoter (-866G>A) modulates mRNA expression, with increased expression associated with the A allele. We investigated association of this variant with coronary artery disease (CAD) in two cohorts of type 2 diabetic subjects. RESEARCH DESIGN AND METHODS-We studied 3,122 subjects from the 6-year prospective Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria, Cardiovascular Events, and Ramipril (DIABHYCAR) Study (14.9% of CAD incidence at follow-up). An independent, hospital-based cohort of 335 men, 52% of whom had CAD, was also studied. RESULTS-We observed an inverse association of the A allele with incident cases of CAD in a dominant model (hazard risk 0.88 [95% CI 0.80-0.96]; P = 0.006). Similar results were observed for baseline cases of CAD. Stratification by sex confirmed an allelic association with CAD in men, whereas no association was observed in women. All CAD phenotypes considered-myocardial infarction, angina pectoris, coronary artery bypass graft (CABG), and sudden death-contributed significantly to the association. Results were replicated in a cross-sectional study of an independent cohort (odds ratio 0.47 [95% CI 0.25-0.89]; P = 0.02 for a recessive model). CONCLUSIONS-The A allele of the -866G>A variant of UCP2 was associated with reduced risk of CAD in men with type 2 diabetes in a 6-year prospective study. Decreased risk of myocardial infarction, angina pectoris, CABG, and sudden death contributed individually and significantly to the reduction of CAD risk. This association was independent of other common CAD risk factors

Results of methotrexate-etoposide-ifosfamide based regimen (M-EI) in osteosarcoma patients included in the French OS2006/sarcome-09 study

International audienceBACKGROUND:In most countries, reference chemotherapy for osteosarcoma is MAP regimen (M = high-dose methotrexate, AP = doxorubicin-cisplatinum). In France, the standard preoperative chemotherapy for children/adolescents combines M and etoposide-ifosfamide (EI), based on the OS94-trial. We report the safety and efficacy results of patients ≤25 years treated with preoperative M-EI regimen enroled in the French OS2006-study, between 2007 and 2014.METHODS:Treatment comprised preoperative chemotherapy with the 7 M-courses and 2 EI-courses, then surgery and postoperative chemotherapy assigned by risk's groups: standard-risk (good histological response without metastases) received 12 M-courses, 3 EI-courses; high-risk (poor histologic response, initial metastases or unresectable primary) received 5 M-courses alternated with 5 AP-courses. 253 patients were randomised to receive (n = 128) or not (n = 125) zoledronate.RESULTS:409/522 patients enroled in the OS2006 study who received preoperative M-EI were analysed. Median age was 14.3 years (4.7-24.5), with 55 patients aged 18-25 years. Primary tumour location was limb in 383 patients (94%) and 85 (21%) presented metastases. Median chemotherapy duration was 37.4 weeks. 381 (96%) patients underwent surgery, 258 patients (65%) had a good histologic response. 187/324 patients (58%) with localised disease did not receive doxorubicin nor cisplatinum. Toxicity was evaluated in the randomised study: most patients experienced ≥1 severe toxicity (grade IV haematological or grade III/IV extra-haematological). Median follow-up was 4.8 years, and 168 patients had events. Five-year event-free survival was 56% (95% CI, 51-62%) and overall survival 71% (66-76%).CONCLUSION:M-EI regimen/strategy was feasible for patient aged ≤25 years with survival rates are comparable to those obtained with MAP regimen

Adapted EXTREME regimen in the first-line treatment of fit, older patients with recurrent or metastatic head and neck squamous cell carcinoma (ELAN-FIT): a multicentre, single-arm, phase 2 trial

International audienceBackgroundA standard treatment for fit, older patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) is yet to be established. In the previous EXTREME trial, few older patients were included. We aimed to evaluate the efficacy and tolerance of an adapted EXTREME regimen in fit, older patients with recurrent or metastatic HNSCC.MethodsThis single-arm, phase 2 study was done at 22 centres in France. Eligible patients were aged 70 years or older and assessed as not frail (fit) using the ELAN Geriatric Evaluation (EGE) and had recurrent or metastatic HNSCC in the first-line setting that was not eligible for local therapy (surgery or radiotherapy), and an Eastern Cooperative Oncology Group performance status of 0–1. The adapted EXTREME regimen consisted of six cycles of fluorouracil 4000 mg/m2 on days 1–4, carboplatin with an area under the curve of 5 on day 1, and cetuximab on days 1, 8, and 15 (400 mg/m2 on cycle 1–day 1, and 250 mg/m2 subsequently), all intravenously, with cycles starting every 21 days. In patients with disease control after two to six cycles, cetuximab 500 mg/m2 was continued once every 2 weeks as maintenance therapy until disease progression or unacceptable toxicity. Granulocyte colony-stimulating factor was systematically administered and erythropoietin was recommended during chemotherapy. The study was based on the two-stage Bryant and Day design, combining efficacy and toxicity endpoints. The primary efficacy endpoint was objective response rate at week 12 after the start of treatment, assessed by central review (with an unacceptable rate of ≤15%). The primary toxicity endpoint was morbidity, defined as grade 4–5 adverse events, or cutaneous rash (grade ≥3) that required cetuximab to be discontinued, during the chemotherapy phase, or a decrease in functional autonomy (Activities of Daily Living score decrease ≥2 points from baseline) at 1 month after the end of chemotherapy (with an unacceptable morbidity rate of >40%). Analysis of the coprimary endpoints, and of safety in the chemotherapy phase, was based on the per-protocol population, defined as eligible patients who received at least one cycle of the adapted EXTREME regimen. Safety in the maintenance phase was assessed in all patients who received at least one dose of cetuximab as maintenance therapy. The study is registered with ClinicalTrials.gov, NCT01864772, and is completed.FindingsBetween Sept 27, 2013, and June 20, 2018, 85 patients were enrolled, of whom 78 were in the per-protocol population. 66 (85%) patients were male and 12 (15%) were female, and the median age was 75 years (IQR 72–79). The median number of chemotherapy cycles received was five (IQR 3–6). Objective response at week 12 was observed in 31 patients (40% [95% CI 30–51]) and morbidity events were observed in 24 patients (31% [22–42]). No fatal adverse events occurred. Four patients presented with a decrease in functional autonomy 1 month after the end of chemotherapy versus baseline. During chemotherapy, the most common grade 3–4 adverse events were haematological events (leukopenia [22 patients; 28%], neutropenia [20; 26%], thrombocytopenia [15; 19%], and anaemia [12; 15%]), oral mucositis (14; 18%), fatigue (11; 14%), rash acneiform (ten; 13%), and hypomagnesaemia (nine; 12%). Among 44 patients who received cetuximab during the maintenance phase, the most common grade 3–4 adverse events were hypomagnesaemia (six patients; 14%) and acneiform rash (six; 14%).InterpretationThe study met its primary objectives on objective response and morbidity, and showed overall survival to be as good as in younger patients treated with standard regimens, indicating that the adapted EXTREME regimen could be used in older patients with recurrent or metastatic HNSCC who are deemed fit with use of a geriatric evaluation tool adapted to patients with head and neck cancer, such as the EGE